Myeloid Neoplasms with Germline DDX41 Mutation

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Primary Author(s)*

Fei Yang, MD, FACMG

Oregon Health & Science University, Portland, OR

Cancer Category/Type

Myeloid Neoplasms with Germline Predisposition

Cancer Sub-Classification / Subtype

Myeloid Neoplasms with Germline DDX41 Mutation

Definition / Description of Disease

This is a distinct entity in the World Health Organization (WHO) classification system within the section of Myeloid Neoplasms with Germline Predisposition[1].

This entity defines cases of myeloid neoplasms, in particular MDS and AML, occur in association with inherited or de novo germline mutations in the DDX41 gene.

Synonyms / Terminology

Familial myeloid neoplasms with germline DDX41 mutation; familial myelodysplastic syndromes/acute leukemias with germline DDX41 mutation

Epidemiology / Prevalence

Myeloid neoplasms with germline DDX41 mutation usually have prolonged latency, with relatively old age at hematological malignancy onset similar to that of the sporadic cases of MDS or AML[2]. Males appear to be predominantly affected. The prevalence of DDX41-related myeloid neoplasms has not been established. It was initially reported in 3-5% of pedigrees with suspected inherited hematological malignancies or familial MDS/AML[3][4]. The most recent study reported an incidence of 2.4% in an un-selected cohort of 1385 patients with MDS or AML[2].

Clinical Features

The initial presentation is usually myeloid disorders without a pre-existing disorder or organ dysfunction. One large cohort study reported about half of the patients with germline DDX41-related MDS/AML had a history of cytopenia several years before overt myeloid neoplasms[2]. Another recent study reported that DDX41 germline mutations were detected in small fraction of individuals with Idiopathic cytopenia of undetermined significance (ICUS)[5]. Some mutations may also predispose to lymphoid malignancies[2][4].

Sites of Involvement

Blood and bone marrow.

Morphologic Features

Patients with germline DDX41 mutation who develop MDS/AML typically showed hypocellular bone marrow, significant neutropenia, and with prominent erythroid and megakaryocytic dysplasia[1][2]. MDS is mainly MDS with multilineage dysplasia (MDS-MLD), MDS with excess blasts (MDS-EB), and MDS with isolated del(5q). AML is frequently present as the erythroblastic subtype (M6) by early report[6]; however, another large cohort study identified subtypes M2, M1, and M0, without M6[2].


No typical immunophenotype is described in the current literature.

Chromosomal Rearrangements (Gene Fusions)

No typical chromosomal rearrangements/gene fusions are described in the current literature.

Characteristic Chromosomal Aberrations / Patterns

Patients with germline DDX41 mutation who develop MDS/AML usually present a normal karyotype, reported at 70-85%[2][6] . Other isolated chromosomal aberrations at low incidence include trisomy 8, deletion of 20q, and abnormalities involving chromosome 7[2][5].

Genomic Gain/Loss/LOH

Deletions of DDX41 locus have been reported in 26% of MDS cases with del(5q)[6].

Gene Mutations (SNV/INDEL)

The reported DDX41 germline mutations include frameshift, missense, nonsense, and splicing mutations. The alterations commonly occur in the ATP binding domain, but could be anywhere throughout the gene. The most common mutations are p.D140Gfs*2 and p.M1I. Approximately half of cases had an acquired DDX41 mutation affecting the remaining wild-type allele, with p.R525H as the most common somatic mutation[2][6].

Other Mutations

Type Gene/Region/Other
Concomitant Mutations TP53, SF3B1, TET2, SMC3, NPM1, ASXL1, EZH2, DNMT3A, SRSF2, and other myeloid genes
Secondary Mutations
Mutually Exclusive

Epigenomics (Methylation)

Not applicable

Genes and Main Pathways Involved

The DDX41 gene, located on the long arm of chromosome 5, encodes a DEAD-box RNA helicase. The Ddx41 protein has several major functional domains: DEAD/ATP binding domain, helicase C-terminal domain, and Zinc finger domain. The Ddx41 protein function and its molecular mechanism leading to hematologic malignancies remain elusive. It has been implicated to play roles in several cellular processes including innate immune response, mRNA splicing, and ribosome biogenesis, as well as to act as a tumor suppressor[6][7]. In innate immunity, DDX41 activity regulates the STING-TBK1-IRF3 pathway in response to viral or bacterial infection[8].

Diagnostic Testing Methods

Myeloid gene panel testing by Next generation sequencing, PCR, Sanger sequencing

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

The prognosis of myeloid neoplasms with germline DDX41 mutation is generally poor[1][6]. Within the high-risk MDS/AML patients, the germline DDX41-mutated patients have a better overall survive compared with the DDX41 wild-type patients[2]. Early data have showed lenalidomide sensitivity in a limited number of patients with DDX41 mutations[6].

Familial Forms

Myeloid neoplasms with germline DDX41 mutation is a rare autosomal dominant disorder. Penetrance has not been well established. Asymptomatic carriers have been reported, suggesting variable penetrance[3][6].

Other Information

Not applicable.




  1. 1.0 1.1 1.2 Peterson LC, et al., (2017). Myeloid neoplasms with germline predisposition, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p125.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Sébert, Marie; et al. (2019). "Germline DDX41 mutations define a significant entity within adult MDS/AML patients". Blood. 134 (17): 1441–1444. doi:10.1182/blood.2019000909. ISSN 1528-0020. PMID 31484648.
  3. 3.0 3.1 Cardoso, S. R.; et al. (2016). "Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia". Leukemia. 30 (10): 2083–2086. doi:10.1038/leu.2016.124. ISSN 1476-5551. PMC 5008455. PMID 27133828.
  4. 4.0 4.1 Lewinsohn, Maya; et al. (2016). "Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies". Blood. 127 (8): 1017–1023. doi:10.1182/blood-2015-10-676098. ISSN 1528-0020. PMC 4968341. PMID 26712909.
  5. 5.0 5.1 Choi, Eun-Ji; et al. (2019). "DDX41 mutation in Patients with Idiopathic Cytopenia of Undetermined Significance, Myelodysplastic Syndrome, and Acute Myeloid Leukemia" Blood. 134(Supplement_1):3002.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Polprasert, Chantana; et al. (2015). "Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms". Cancer Cell. 27 (5): 658–670. doi:10.1016/j.ccell.2015.03.017. ISSN 1878-3686. PMID 25920683.
  7. Omura, Hiroki; et al. (2016). "Structural and Functional Analysis of DDX41: a bispecific immune receptor for DNA and cyclic dinucleotide". Scientific Reports. 6: 34756. doi:10.1038/srep34756. ISSN 2045-2322. PMC 5056382. PMID 27721487.
  8. Jiang, Yan; et al. (2017). "The emerging roles of the DDX41 protein in immunity and diseases". Protein & Cell. 8 (2): 83–89. doi:10.1007/s13238-016-0303-4. ISSN 1674-8018. PMC 5291771. PMID 27502187.


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*Citation of this Page: Yang F. “Myeloid Neoplasms with Germline DDX41 Mutation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/2/2021,